Neonatal hypoxic-ischemic encephalopathy (HIE) refers to brain injury resulting from reduced blood and oxygen flow to a baby's brain near the time of birth. HIE affects up to 12,000 newborns each year in the U.S. Half of affected infants have a bad outcome including death, cerebral palsy and cognitive impairment despite receiving hypothermia, the only available treatment. Cerebral palsy is the most common long term neurodevelopmental impairment in survivors of HIE. Each year in the U.S., new cases of HIE resulting in cerebral palsy impose an estimated economic burden of $1.7 billion in lifetime costs. Erythropoietin (Epo) is a cytokine with remarkable neuroprotective and neuroregenerative effects demonstrated in animal models of neonatal brain injury. Epo reduces apoptotic, inflammatory and oxidative brain injury following hypoxia- ischemia, and enhances neurogenesis and oligodendrocyte survival, promoting brain regeneration and improved function. In non-human primates, Epo reduces the rate of cerebral palsy and improves neurologic function in animals undergoing hypothermia for HIE. Small human trials suggest that infants with HIE treated with Epo have better neurologic outcomes. In our phase I trial of Epo + hypothermia, we found that Epo 1000 U/Kg/dose best reproduced the pharmacokinetics of neuroprotective dosing in animal models. Long term outcomes were better than expected based on entry criteria and MRI findings. Our phase II trial compared 50 cooled infants randomized to receive Epo or placebo. Infants treated with hypothermia + Epo had less brain injury on early MRI, and better 6-month developmental outcome based on a standardized parental questionnaire. Epo is commercially available, relatively inexpensive, and safe in neonates. We hypothesize that Epo given to cooled infants with moderate/severe HIE will reduce the combined primary outcome of death or neurodevelopmental impairment from 49 to 33%. To test this hypothesis, we propose a randomized, double- blind, placebo-controlled trial of Epo therapy in 500 infants with HIE undergoing hypothermia. Our specific aims are 1) To determine if 5 doses of Epo 1000 U/kg IV reduces the rate of death, motor or cognitive deficits at 2 years; 2) To assess safety of Epo by evaluating clinical toxicity; and 3) To determine whether Epo decreases the severity of neonatal brain injury as evidenced by early MRI and circulating biomarkers of brain injury. Motor outcome will be determined by a standardized neurologic exam and by the Gross Motor Function Classification System. Cognitive outcome will be determined by Bayley III exam. In secondary analyses, we will examine the effect of Epo on cerebral palsy, severity of motor impairment, Bayley III cognitive and language scores, epilepsy and behavioral abnormalities. We anticipate that Epo will confer improved 2-year neurodevelopmental outcome, will be safe, and will decrease brain injury severity as determined by early biomarkers. The DCC will lead protocol development, data collection, quality assurance, participant management systems, interim and final data analysis, and manuscript preparation. The DCC application is linked with the CCC application.